Cancer Cell Membrane-Coated Homodimer Prodrug Nanoassemblies to Simultaneously Deliver Prodrugs and Immune Adjuvants for Combined Chemo-Immunotherapy

Homodimer prodrug nanoassemblies (HPNAs) gain significant attention due to their ultrahigh drug-loading capacity and carrier-free nature but suffer from poor self-assembly stability and rapid clearance from blood circulation. Cell membranes prove as a promising coating material for nanoparticle modification, offering specialized properties such as specific recognition, prolonged circulation time, and immune evasion. Here, we present a cancer cell membrane-modified biomimetic nanoassembly system designed for combined chemo-immunotherapy. We design a paclitaxel dimer-based small-molecule self-assembling prodrug, PTX-STeS-PTX (PSTeSP). The biomimetic nanoassemblies are constructed by using R848/PSTeSP nanoassemblies (RPNAs) to create a nanocore with an outer layer modified by cancer cell membranes (CCM), abbreviated as CCM-coated RPNAs (RP@CCM NAs). The CCM modification improves the stability of RPNAs in blood circulation and increases their accumulation at tumor sites. Additionally, CCM-coated RPNAs exhibit enhanced homologous targeting specificity toward cancer cells, significantly promoting cellular uptake and selectively inducing cytotoxicity in tumor cells. Furthermore, the incorporation of R848 into the PSTeSP-based nanoassemblies enhances the immune complexity at tumor sites, reshapes the tumor immune microenvironment, and inhibits cancer cell metastasis, enabling a combined chemotherapy and immunotherapy approach. This study explores the potential of CCM as a surface modification material to enhance the pharmacokinetic profile and tumor-specific targeting of HPNAs, offering a rational strategy for HPNA-based drug delivery systems in effective cancer treatment.